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Transcriptome alteration in the diabetic heart by rosiglitazone: implications for cardiovascular mortality.

Wilson KD, Li Z, Wagner R, Yue P, Tsao P, Nestorova G, Huang M, Hirschberg DL, Yock PG, Quertermous T, Wu JC - PLoS ONE (2008)

Bottom Line: Specifically, the cumulative upregulation of (1) a matrix metalloproteinase gene that has previously been implicated in plaque rupture, (2) potassium channel genes involved in membrane potential maintenance and action potential generation, and (3) sphingolipid and ceramide metabolism-related genes, together give cause for concern over rosiglitazone's safety.Lastly, in vivo imaging studies revealed minimal differences between rosiglitazone-treated and untreated db/db mouse hearts, indicating that rosiglitazone's effects on gene expression in the heart do not immediately turn into detectable gross functional changes.A smaller number of unique and interesting changes in gene expression were noted with rosiglitazone treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, Stanford University School of Medicine, Stanford, California, United States of America.

ABSTRACT

Background: Recently, the type 2 diabetes medication, rosiglitazone, has come under scrutiny for possibly increasing the risk of cardiac disease and death. To investigate the effects of rosiglitazone on the diabetic heart, we performed cardiac transcriptional profiling and imaging studies of a murine model of type 2 diabetes, the C57BL/KLS-lepr(db)/lepr(db) (db/db) mouse.

Methods and findings: We compared cardiac gene expression profiles from three groups: untreated db/db mice, db/db mice after rosiglitazone treatment, and non-diabetic db/+ mice. Prior to sacrifice, we also performed cardiac magnetic resonance (CMR) and echocardiography. As expected, overall the db/db gene expression signature was markedly different from control, but to our surprise was not significantly reversed with rosiglitazone. In particular, we have uncovered a number of rosiglitazone modulated genes and pathways that may play a role in the pathophysiology of the increase in cardiac mortality as seen in several recent meta-analyses. Specifically, the cumulative upregulation of (1) a matrix metalloproteinase gene that has previously been implicated in plaque rupture, (2) potassium channel genes involved in membrane potential maintenance and action potential generation, and (3) sphingolipid and ceramide metabolism-related genes, together give cause for concern over rosiglitazone's safety. Lastly, in vivo imaging studies revealed minimal differences between rosiglitazone-treated and untreated db/db mouse hearts, indicating that rosiglitazone's effects on gene expression in the heart do not immediately turn into detectable gross functional changes.

Conclusions: This study maps the genomic expression patterns in the hearts of the db/db murine model of diabetes and illustrates the impact of rosiglitazone on these patterns. The db/db gene expression signature was markedly different from control, and was not reversed with rosiglitazone. A smaller number of unique and interesting changes in gene expression were noted with rosiglitazone treatment. Further study of these genes and molecular pathways will provide important insights into the cardiac decompensation associated with both diabetes and rosiglitazone treatment.

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Related in: MedlinePlus

Multidimensional scaling plot of the expression data and real-time PCR analysis.(A) 3-dimensional scaling plot provides a graphical representation of high-dimensional expression data in low dimensions. Each point within a “cloud” represents a single microarray, and the similarity within a set of microarrays is indicated by their physical proximity to one other. As evidenced from the figure, each group (db/+ control, untreated db/db, and rosiglitazone-treated db/db) clusters into a distinct grouping, indicating that each group has a similar transcriptome that can be distinguished from the two other groups. Taqman real-time PCR of four selected genes normalized to 18s shows (B) significant upregulation of Kcnk1 in untreated db/db vs. db/+ mice and (C) significant upregulation of all four genes in rosiglitazone-treated vs. untreated db/db mice. These data confirm the altered regulatory patterns of these four genes in the microarray data. Values are mean±SEM. *P<0.05 vs. control.
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pone-0002609-g005: Multidimensional scaling plot of the expression data and real-time PCR analysis.(A) 3-dimensional scaling plot provides a graphical representation of high-dimensional expression data in low dimensions. Each point within a “cloud” represents a single microarray, and the similarity within a set of microarrays is indicated by their physical proximity to one other. As evidenced from the figure, each group (db/+ control, untreated db/db, and rosiglitazone-treated db/db) clusters into a distinct grouping, indicating that each group has a similar transcriptome that can be distinguished from the two other groups. Taqman real-time PCR of four selected genes normalized to 18s shows (B) significant upregulation of Kcnk1 in untreated db/db vs. db/+ mice and (C) significant upregulation of all four genes in rosiglitazone-treated vs. untreated db/db mice. These data confirm the altered regulatory patterns of these four genes in the microarray data. Values are mean±SEM. *P<0.05 vs. control.

Mentions: Whole-heart RNA from five mice from each of the three groups after four months with or without treatment was used for microarray analysis. Overall, there were significant transcriptional differences between the db/+ and both db/db groups, while differences between rosiglitazone-treated and untreated db/db groups were much less dramatic. Figure 5a shows a 3-dimensional scaling plot based on principal component analysis of the expression data, which graphically demonstrates that rosiglitazone did not restore db/db transcriptomes to the normal db/+ state.


Transcriptome alteration in the diabetic heart by rosiglitazone: implications for cardiovascular mortality.

Wilson KD, Li Z, Wagner R, Yue P, Tsao P, Nestorova G, Huang M, Hirschberg DL, Yock PG, Quertermous T, Wu JC - PLoS ONE (2008)

Multidimensional scaling plot of the expression data and real-time PCR analysis.(A) 3-dimensional scaling plot provides a graphical representation of high-dimensional expression data in low dimensions. Each point within a “cloud” represents a single microarray, and the similarity within a set of microarrays is indicated by their physical proximity to one other. As evidenced from the figure, each group (db/+ control, untreated db/db, and rosiglitazone-treated db/db) clusters into a distinct grouping, indicating that each group has a similar transcriptome that can be distinguished from the two other groups. Taqman real-time PCR of four selected genes normalized to 18s shows (B) significant upregulation of Kcnk1 in untreated db/db vs. db/+ mice and (C) significant upregulation of all four genes in rosiglitazone-treated vs. untreated db/db mice. These data confirm the altered regulatory patterns of these four genes in the microarray data. Values are mean±SEM. *P<0.05 vs. control.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2481284&req=5

pone-0002609-g005: Multidimensional scaling plot of the expression data and real-time PCR analysis.(A) 3-dimensional scaling plot provides a graphical representation of high-dimensional expression data in low dimensions. Each point within a “cloud” represents a single microarray, and the similarity within a set of microarrays is indicated by their physical proximity to one other. As evidenced from the figure, each group (db/+ control, untreated db/db, and rosiglitazone-treated db/db) clusters into a distinct grouping, indicating that each group has a similar transcriptome that can be distinguished from the two other groups. Taqman real-time PCR of four selected genes normalized to 18s shows (B) significant upregulation of Kcnk1 in untreated db/db vs. db/+ mice and (C) significant upregulation of all four genes in rosiglitazone-treated vs. untreated db/db mice. These data confirm the altered regulatory patterns of these four genes in the microarray data. Values are mean±SEM. *P<0.05 vs. control.
Mentions: Whole-heart RNA from five mice from each of the three groups after four months with or without treatment was used for microarray analysis. Overall, there were significant transcriptional differences between the db/+ and both db/db groups, while differences between rosiglitazone-treated and untreated db/db groups were much less dramatic. Figure 5a shows a 3-dimensional scaling plot based on principal component analysis of the expression data, which graphically demonstrates that rosiglitazone did not restore db/db transcriptomes to the normal db/+ state.

Bottom Line: Specifically, the cumulative upregulation of (1) a matrix metalloproteinase gene that has previously been implicated in plaque rupture, (2) potassium channel genes involved in membrane potential maintenance and action potential generation, and (3) sphingolipid and ceramide metabolism-related genes, together give cause for concern over rosiglitazone's safety.Lastly, in vivo imaging studies revealed minimal differences between rosiglitazone-treated and untreated db/db mouse hearts, indicating that rosiglitazone's effects on gene expression in the heart do not immediately turn into detectable gross functional changes.A smaller number of unique and interesting changes in gene expression were noted with rosiglitazone treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, Stanford University School of Medicine, Stanford, California, United States of America.

ABSTRACT

Background: Recently, the type 2 diabetes medication, rosiglitazone, has come under scrutiny for possibly increasing the risk of cardiac disease and death. To investigate the effects of rosiglitazone on the diabetic heart, we performed cardiac transcriptional profiling and imaging studies of a murine model of type 2 diabetes, the C57BL/KLS-lepr(db)/lepr(db) (db/db) mouse.

Methods and findings: We compared cardiac gene expression profiles from three groups: untreated db/db mice, db/db mice after rosiglitazone treatment, and non-diabetic db/+ mice. Prior to sacrifice, we also performed cardiac magnetic resonance (CMR) and echocardiography. As expected, overall the db/db gene expression signature was markedly different from control, but to our surprise was not significantly reversed with rosiglitazone. In particular, we have uncovered a number of rosiglitazone modulated genes and pathways that may play a role in the pathophysiology of the increase in cardiac mortality as seen in several recent meta-analyses. Specifically, the cumulative upregulation of (1) a matrix metalloproteinase gene that has previously been implicated in plaque rupture, (2) potassium channel genes involved in membrane potential maintenance and action potential generation, and (3) sphingolipid and ceramide metabolism-related genes, together give cause for concern over rosiglitazone's safety. Lastly, in vivo imaging studies revealed minimal differences between rosiglitazone-treated and untreated db/db mouse hearts, indicating that rosiglitazone's effects on gene expression in the heart do not immediately turn into detectable gross functional changes.

Conclusions: This study maps the genomic expression patterns in the hearts of the db/db murine model of diabetes and illustrates the impact of rosiglitazone on these patterns. The db/db gene expression signature was markedly different from control, and was not reversed with rosiglitazone. A smaller number of unique and interesting changes in gene expression were noted with rosiglitazone treatment. Further study of these genes and molecular pathways will provide important insights into the cardiac decompensation associated with both diabetes and rosiglitazone treatment.

Show MeSH
Related in: MedlinePlus